Novel method for synthesis of (2s, 3as, 7as)-1-{(s)-alanyl}-octahydro-1h-indole-2-carboxylic acid derivatives and use for synthesis of perindopril

ABSTRACT

Process for the industrial synthesis of the compounds of formula (I):  
                 
 
     wherein R 1  represents a hydrogen atom or an alkyl or benzyl group, and R 2  represents a group that protects the amino function.  
     Application in the synthesis of perindopril and of its pharmaceutically acceptable salts.

[0001] The present invention relates to a process for the industrialsynthesis of compounds of formula (I):

[0002] wherein R₁ represents a hydrogen atom, a linear or branched(C₁-C₆)alkyl group or a benzyl group, and R₂ represents a group thatprotects the amino function,

[0003] and to their application in the industrial synthesis ofperindopril of formula (II):

[0004] and of its pharmaceutically acceptable salts.

[0005] Perindopril, and also pharmaceutically acceptable salts thereof,and more especially the tert-butylamine salt thereof, have valuablepharmacological properties.

[0006] Their principal property lies in the inhibition of the enzymethat converts angiotensin I (or kininase II), which enables on the onehand prevention of the conversion of the decapeptide angiotensin I tothe octapeptide angiotensin II (vasoconstrictor), and on the other handprevention of the degradation of bradykinin (vasodilator) to inactivepeptide. Those two actions contribute to the beneficial effects ofperindopril in cardiovascular disorders, especially arterialhypertension and cardiac insufficiency.

[0007] Perindopril, its preparation and its therapeutic use have beendescribed in European Patent EP0049658.

[0008] Given the pharmaceutical value of that compound, it is importantto be able to obtain it by an effective industrial synthesising processthat can readily be applied on an industrial scale, yielding perindoprilin a good yield and, especially, with an excellent degree of purity.

[0009] Patent Specification EP 0 308 341 describes the industrialsynthesis of perindopril by catalytic hydrogenation of(2S)-2,3-dihydroindole-2-carboxylic acid, followed by coupling of theresulting (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl esterwith N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester, and thendeprotection of the carboxylic group of the heterocycle by catalytichydrogenation.

[0010] That process has the advantage of yielding perindopril in a goodyield. However, the purity of the perindopril obtained by that processis not satisfactory, and necessitates a purification step in order toobtain perindopril of a quality that would allow its use as apharmaceutical active ingredient.

[0011] Indeed, under the conditions described in that patentspecification the perindopril obtained is contaminated by significantamounts of the impurities of formulae (III) and (IV):

[0012] The Applicant has now developed a new industrial synthesisingprocess that, without requiring laborious purification, yieldsperindopril of a purity that is compatible with its use as apharmaceutical active ingredient, and that is, for example, totally freeof the impurities of formulae (III) and (IV).

[0013] Moreover, the process uses alanine as its source of chirality,alanine being a natural and, accordingly, inexpensive starting material.

[0014] More specifically, the present invention relates to a process forthe industrial synthesis of the compound of formula (I):

[0015] wherein R₁ represents a hydrogen atom, a linear or branched(C₁-C₆)alkyl group or a benzyl group, and R₂ represents a group thatprotects the amino function,

[0016] characterised in that the ester of formula (V)

[0017] wherein R₁ is as defined for formula (I),

[0018] is reacted with the alanine compound of formula (VI):

[0019] wherein R₂ is as defined for formula (I),

[0020] in an organic solvent, such as, for example, tetrahydrofuran orethyl acetate,

[0021] in the absence of 1-hydroxybenzotriazole or in the presence of anamount of less than 0.6 mol of 1-hydroxybenzotriazole per mol ofcompound of formula (V) employed, in the presence of an amount of from 1to 1.2 mol of dicyclohexylcarbodiimide per mol of compound of formula(V) employed, and in the presence of an amount of from 1 to 1.2 mol oftriethylamine per mol of compound of formula (V) employed,

[0022] at a temperature of from 20 to 50° C.,

[0023] to yield, after isolation and then recrystallisation, thecompound of formula (VII):

[0024] wherein R₁ and R₂ are as defined hereinbefore,

[0025] which is hydrogenated in the presence of a catalyst, such as, forexample, Pd/C, Rh/C, Pt/C, Ni/C or PtO₂,

[0026] under a hydrogen pressure of from 1 to 40 bars, at a temperatureof from 30 to 70° C., to yield the compound of formula (I).

[0027] The compound of formula (I) so obtained is then subjected, whereappropriate, to a reaction for the deprotection of the acid and aminefunctions, followed by a coupling reaction, either with ethyl2-oxo-pentanoate under conditions of reductive amination,

[0028] or with a compound of formula (XII):

[0029] wherein X represents a leaving group selected from a halogenatom,

—O—SO₂CH₃

and

[0030] to yield optically pure perindopril, which is converted, ifdesired, into a pharmaceutically acceptable salt such as thetert-butylamine salt.

[0031] The process is of particular interest for the following reasons:

[0032] The coupling in alkaline medium of the (2S, 3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester of formula (VIII)

[0033] with the compound of formula (IX) has been described in PatentSpecification EP 0 308 341.

[0034] However, the perindopril benzyl ester so obtained is contaminatedby a number of by-products.

[0035] In particular, it contains significant amounts (5 to 15%) of theimpurities of formulae (X) and (XI) resulting from the reaction of thecoupling product with dicyclohexylcarbodiimide, which impurities, afterdebenzylation, yield the impurities of formulae (III) and (IV).

[0036] The Applicant has found that the coupling reaction of thecompound of formula (V) with the compound of formula (VI) yields acompound of formula (VII) that is totally free of the impuritiesresulting from the reaction of the coupling product withdicyclohexylcarbodiimide.

[0037] The compound of formula (VII) so obtained yields perindopril offar better purity, and that is in particular totally free of theimpurities of formulae (III) and (IV).

[0038] Moreover, the Applicant has found that it was possible to obtainthe intermediate compound of formula (VII) in a crystalline form thatwas readily purifiable. Its conversion according to the process of theinvention thus yields the compound of formula (I) in excellent purity.

[0039] The Examples below illustrate the invention, but do not limit itin any way.

EXAMPLE 1Methyl(2S)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-2,3-dihydro-1H-indole-2-carboxylate

[0040] There are introduced into a reactor, with stirring, 2.13 kg ofmethyl(2S)-2,3-dihydroindole-2-carboxylate, 1 kg of triethylamine, 30litres of tetrahydrofuran and then, after 10 minutes' stirring at roomtemperature, 1.9 kg of N-[tert-butyloxycarbonyl]-(S)-alanine and 2 kg ofdicyclohexylcarbodiimide. The heterogeneous mixture is then stirred atroom temperature for 6 hours, and is subsequently cooled to 0° C. andfiltered.

[0041] The filtrate is then washed and recrystallised from a mixture ofhexane/ethyl acetate 10/1 to yield the expected product in a yield of81% and with a chemical purity of 98%.

[0042] Melting Point: 130-131° C.

[0043] Elemental Microanalysis: C% H% N% calculated 62.05 6.94 8.04found 61.80 6.94 8.00

EXAMPLE 2 Methyl(2S, 3aS,7aS)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylate/method1

[0044] The residue obtained in Example 1 (1 kg) is dissolved in methanoland transferred to a hydrogenator, and then 0.10 kg of 5%rhodium-on-carbon is added.

[0045] The mixture is then hydrogenated under a pressure of 30 bars, ata temperature of 60° C., until absorption of the theoretical amount ofhydrogen.

[0046] After removal of the catalyst by filtration, the solvent isremoved by evaporation to yield the expected product in a yield of 90%and with a chemical purity of 98%.

EXAMPLE 3 Methyl(2S, 3aS,7aS)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylate/method2

[0047] The residue obtained in Example 1 (1 kg) is dissolved in aceticacid and transferred to a hydrogenator, and then 0.10 kg of platinumdioxide is added.

[0048] The mixture is then hydrogenated under a pressure of 10 bars at atemperature of 40° C., until absorption of the theoretical amount ofhydrogen.

[0049] After removal of the catalyst by filtration, the solvent isremoved by evaporation to yield the expected product in a yield of 90%and with a chemical purity of 98%.

1-6. (canceled)
 7. A process for the industrial synthesis of a compoundselected from those of formula (I):

wherein R₁ represents hydrogen, linear or branched (C₁-C₆)alkyl orbenzyl, and R₂ represents a group that protects the amino function,wherein the ester of formula (V)

is reacted with the alanine compound of formula (VI):

in an organic solvent in the absence of 1-hydroxybenzotriazole or in thepresence of an amount of less than 0.6 mol of 1-hydroxybenzotriazole permol of compound of formula (V) employed, in the presence of an amount of1 to 1.2 mol of dicyclohexylcarbodiimide per mol of compound of formula(V) employed, and in the presence of an amount of 1 to 1.2 mol oftriethylamine per mol of compound of formula (V) employed, at atemperature of 20 to 50° C., to yield, after isolation and thenrecrystallisation, the compound of formula (VII):

which is hydrogenated in the presence of a catalyst under a hydrogenpressure of 1 to 40 bars, at a temperature of 30 to 70° C., to yield thecompound of formula (I).
 8. A process according to claim 7, wherein theorganic solvent is selected from tetrahydrofuran or ethyl acetate.
 9. Aprocess according to claim 7, wherein the catalyst is selected fromPd/C, Rh/C, Pt/C, Ni/C or PtO₂.
 10. A process according to claim 9,wherein the catalyst employed in the hydrogenation step isrhodium-on-carbon.
 11. A process according to claim 9, wherein thecatalyst employed in the hydrogenation step is platinum dioxide.
 12. Aprocess according to claim 7, wherein R₁ represents methyl.
 13. Processfor the synthesis of perindopril or pharmaceutically acceptable saltsthereof, using a compound of formula (I) obtained by he process of claim7.
 14. Process of claim 13 wherein the resulting perindopril is free ofthe impurities of formulae (III) and (IV).